A shot in the arm for water treatment

Water used in injections and infusions must be apyrogenic. Gary Walters* highlights the processes involved in keeping the water free from pyrogens and other contaminants

Of the various qualities of water used in the pharmaceutical industry, by far the most critical is water for injection (WFI). This is the quality of water that is used for manufacturing parenteral solutions — vaccines, intravenous drips and similar products — which come directly into contact with a patient's blood. It is essential that there are no contaminants in the water which are toxic or could interfere with the therapeutic effect of the product.

Quality standards are set by the various national pharmacopoeia to this end. The requirements of the current editions of the United States (USP), European (EP) and Japanese (JP) pharmacopoeia are summarised in Table 1. The British Pharmacopoeia is now in line with EP. Pharmaceutical companies worldwide manufacture their products either for sale in, or to the requirements of, the US market and this has made the United States Pharmacopoeia the de facto international quality standard for pharmaceutical purified water and WFI. Other national standards are generally evolving to reflect this.

Traditionally, all the pharmacopoeia specified water quality by a series of laboratory tests. Perhaps the most significant change in water quality specifications has been the adoption by the USP, and subsequently by EP, of conductivity as the measure of ionic contaminants instead of the traditional wet chemistry. This measurement procedure, however, is not as straightforward as might be assumed.

controlling pyrogens

The need for low bacterial counts is obvious, since bacteria could introduce infection into the blood. But this itself is not sufficient, as the water must also be apyrogenic. Pyrogens are substances that when injected into the blood, cause a fever to develop in the patient. They are mostly endotoxins — large protein molecules produced by bacterial metabolism or cell breakdown. The principal source is from Gram negative bacteria such as Escherichia coli, Streptococcus faecalis, Clostridium welchii and Pseudomonas spp. It is this need for apyrogenicity which differentiates WFI from the less stringent standards for purified water.

Some pyrogen molecules are decomposed at temperatures above 120°C. This temperature also ensures sterility of the water, and older editions of all pharmacopoeia specified that WFI should be produced by distillation. However, because of the size of endotoxin molecules, both ultrafiltration, with a molecular weight cut off at 6000, and reverse osmosis, which has an effective molecular weight cut off at about 200, are capable of producing pyrogen free water.

JP allows the use of either process as an alternative to distillation for production of WFI, USP allows the use of reverse osmosis but BP and EP still insist that WFI should be distilled. Pharmaceutical stills are high in capital cost, and they are expensive to use because they must be fed with purified water, which has to meet the same chemical purity standards as WFI, and be supplied with clean steam as a heating medium.

lower capital costs

Membrane systems are lower both in capital and operating costs, and there is an economic argument for using membranes to produce 'pyrogen-free water' for use in high consumption non-product applications such as vial washing and reactor cleaning, reserving distilled WFI for use as a product ingredient only.

Vivendi Water Systems has over 20 years of experience in the use of membrane processes for pharmaceutical water production. Table 2 sets out the output pyrogen levels expected in purified water by the various production methods.

Manufacturing installations producing pharmaceuticals for the US market are subject to inspection by the FDA. In the case of WFI systems, this means compliance with USP, but the USP does not currently set a maximum limit for the bacteria count but offers a guide value of 0.1cfu/ml. The FDA is, therefore, concerned that the bacteria levels in the WFI system are under control. The user needs to assure the FDA that the bacteria levels are both low and relatively static, and that alert and action levels are set, together with documented actions which must be taken on reaching these levels.

ensuring cleanliness in storage

It is one challenge to produce apyrogenic water, but quite another to ensure that it remains apyrogenic during storage and distribution to the point-of-use. This is a matter of system design and housekeeping. The pharmaceutical industry is largely based on batch processing, which means that water is required intermittently but at high flow rates in order to fill reactors.

Water treatment plants perform best when they are operated continuously, as their capital cost is a function of the maximum flow rate. The result is that water treatment systems are designed to operate continuously at an average flow to top up a storage tank from which reactors are filled, via a recirculating distribution system, as required. As a result, there are often quite long periods when there is no demand for water, during which the water is in storage and recirculation. If the water stagnates during this period, then it can lead to increased pyrogen levels. Airborne contamination can also lead to increased pyrogen levels.

Bacteria proliferate in stagnant areas and dead legs, so careful pipework design and continuous recirculation of WFI via a ring main are essential prerequisites of a storage and distribution system. There are two options: hot or cold systems.

hot distribution systems

Hot distribution systems are appropriate when distillation is used for WFI production. The hot distilled product is maintained at a temperature of 80;90°C during storage and distribution by means of a steam heat exchanger which compensates for heat losses. At temperatures above 80°C, bacterial activity is virtually non-existent and the water remains almost sterile. Although there are no chemical hazards, the tanks and pipes need to be lagged, for both personnel protection and to reduce heat losses. Further, point-of-use cooling will be needed unless all the water is used hot. This makes the capital cost of the system high, but housekeeping is simplified.

Hot water recirculating systems need to be further sanitised if contamination is found in the system. This is most frequently carried out with the use of live clean steam. The system is drained of water and then clean steam is introduced into the system and it is allowed to fill the system and raise the temperature to in excess of 100°C, sometimes up to 121°C. The system is steamed through, with all low points and take-off points opened and steam traps fitted to ensure that any condensate formed is removed from the system. The system is steamed for one hour before WFI water is reintroduced to the recirculating ring.

Cold WFI systems are relatively rare compared with hot ones and need careful monitoring and good housekeeping. Even with bacterial air-vent filters or nitrogen blanketing on the tank, it is almost inevitable that bacteria will enter the system, so routine monitoring is essential. Provided that the temperature is kept low, proliferation of bacteria will be reduced. At temperatures down to 10°C, bacterial growth is minimised. Many purified water systems are operated at cold temperatures and maintained below 25°C.

Cold water systems may need a chilled water-cooled heat exchanger to eliminate the heat generated by pumping. The inclusion of an ultraviolet disinfection unit in cold circulating system provides further protection against bacteria and, since UV irradiation generates some free hydroxide radicals, will provide some oxidation of any pyrogens that are produced.

Bacterial levels can increase dramatically when the system is not in use for an extended period, and this will impact on the pyrogen levels. When this reaches an unacceptable level, the system must be taken out of service and sanitised. Most systems now incorporate automatic sanitisation which can usually be carried out overnight using either heat or ozone.

Heat sanitisation is simple. On initiation of the sanitisation cycle, a steam heat exchanger in the ring main is started and the circulating water is heated to around 85°C and held at that temperature for, typically, one hour before cooling using a chilled water heat exchanger.

Temperature sensors in the pipework detect and record that sanitisation has been achieved so the process can be validated in accordance with cGMP.

Unfortunately, large systems have a high heat capacity and the heat-up and cool-down times can be long. Also, the pipework should be lagged for personnel protection, adding to the capital cost of the system.

pipework sanitisation

End-users are increasingly considering ozone sanitisation as a solution. It offers a shorter sanitisation cycle and operates at ambient temperature. Because ozone is destroyed by ultraviolet light, UV disinfection units have to be switched off prior to distribution loop sanitisation. Ozone is generated on-site using a membrane electrolytic cell fed with purified water.

The resulting ozonated water is fed to the storage tank, where it mixes with the circulating water. Ozone monitors ensure that the appropriate ozone concentration (typically 0.2 mg/l to 0.5mg/l) has been reached at all points in the system and records the ozone concentration for validation purposes.

Once pipework sanitisation has been effected, the disinfecting unit is switched on to destroy the residual ozone in the distribution loop. This, again, is monitored and recorded automatically. Some pharmaceutical companies have found that bacterial control is improved by continuously dosing ozone to the storage tank at about 0.2mg/l and removing the residual ozone by means of the UV unit in the ring main.

preventative maintenance

Sanitisation is then carried out by simply switching off the UV unit. This, of course, increases the operating costs but it also extends the time between sanitisations, reducing the downtime in a three shift production plant.

Vivendi Water Systems has also found that the incorporation of a full flow Ultracept ultrafiltration unit in the ring main greatly extends the periods between sanitisations by removing both bacteria and pyrogens. The Ultracept uses membranes that can be sterilised by steam or hot water and so can remain in the circuit during heat sanitisation.

As with any complex machine or system, a comprehensive programme of maintenance can greatly affect not only the quality of the product, but also the cost of producing that product.

A preventative programme of maintenance that satisfies all regulatory requirements instead of a reactive response is seen as preferable.

Vivendi offers a performance qualified maintenance contract (PQMC), which is supported by a large number of field service engineers, thereby guaranteeing a solution that is fast, reliable and satisfies all relevant validation requirements.

In conclusion, a combination of the right treatment process — membranes or distillation — together with good system design using either hot or cold recirculation, heat or ozone sanitation and good housekeeping will ensure that WFI standards are consistently met.

By working closely during the design stage of an installation project with the customer, the water treatment specialist and the storage and distribution system designer, the responsibility for system performance is shared.

long term performance

This interdependence of design and operation is important, and there must be full agreement between the technical specialists and the end-user before the system design is settled. In this way, with all parties using the system, the long term performance is assured.